Encapsulation of pharmaceuticals in biocompatible, biodegradable polymer microparticles can prolong the maintenance of therapeutic drug levels relative to administration of the drug itself. Sustained release may be extended up to several months depending on the formulation and the active molecule encapsulated. In order to prolong the existence at the target site, the drug may be formulated within a matrix into a slow release formulation. Following administration, the drug then is released via diffusion out of, or via erosion of, the matrix. Encapsulation within biocompatible, biodegradable polyesters, such as, for example, copolymers of lactide and glycolide, has been utilized to deliver small molecule therapeutics ranging from insoluble steroids to small peptides. Presently, there are over a dozen lactide/glycolide polymer formulations in the marketplace, the majority of which are in the form of microparticles.
In addition, U.S. Pat. No. 6,706,289, hereby incorporated in its entirety by reference, discloses controlled release formulations of biologically active molecules that are coupled to hydrophilic polymers such as polyethylene glycol and methods of their production. The formulations are based on solid microparticles formed of the combination of biodegradable polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and copolymers thereof.
Several techniques for the production of microparticles containing biological or chemical agents by an emulsion-based manufacturing technique have been reported. In general, the methods have a first phase consisting of an organic solvent, a polymer and a biological or chemical agent dissolved or dispersed in the first solvent. The second phase comprises water and a stabilizer and, optionally, the first solvent. The first and the second phases are emulsified and, after an emulsion is formed, the first solvent is removed from the emulsion, producing hardened microparticles.
In one technique, two immiscible solutions are added to a packed bed of spherical beads within an emulsion column. Ideally, the two solutions have a combined mass flow rate that creates laminar flow conditions. The flow of the solutions is repeatedly divided and recombined to create homogenous fluid volumes that contain a portion of each immiscible solution. The lesser portion separates into spherical droplets as a dispersed phase in the larger portion (the continuous phase). The repeated division and recombination is critical to the formation of the homogenate.
As the above technique is adjusted to a larger scale, there is a parametric increase in the potential path length that must be traveled by each fluid element. These increases in path length lead to increases in the residence time of the fluid elements in the packed bed emulsion column. The increases in residence time, in turn, can impact the physical properties of the final emulsion product.
Another problem that arises during scale up of a packed bed emulsion column is the formation of preferred channels for fluid travel within the packed bed. The formation of preferred channels leads to “virtual columns,” through which flow is increased relative to a mean flow rate, and “static areas,” where flow is decreased relative to the mean flow rate. The presence of these “virtual columns” and “static areas” impacts the number of homogenization events and other parameters of emulsion formation.
Thus, easily scalable apparatus and methods are needed for forming emulsion-based microparticles that provide a narrow, reproducible, particle size distribution, capable of use with both large and small volumes. More particularly, there is a need in the pertinent art for a column that is configured to maintain a consistent path length and to prevent formation of preferred channels in a packed bed during scale-up of an emulsion process.